A multicenter case-control study on postoperative intestinal fistula in Chinese patients with Crohn disease

The aim of this study was to (1) assess the independent factors affecting patients with postoperative intestinal fistula from Crohn disease (CD) by analyzing preoperative clinical data, (2) establish a nomogram prediction model for this condition based on these factors, and (3) validate this model and evaluate its accuracy. In this retrospective multicenter case-control study, the clinical data of 240 patients with CD admitted for surgical treatment between September 2019 and September 2021 at 3 centers were collected. Patients were randomly divided into a training set (168 patients) and a validation set (72 patients). Univariate analysis was performed for relevant factors, and statistically significant factors were then analyzed using multivariate logistic regression to determine the independent influencing factors. A nomogram model for predicting postoperative intestinal fistula in patients with CD was constructed and the accuracy of the model was evaluated using calibration curves. Univariate analysis showed that disease behavior, abdominal abscess, intestinal perforation, neutrophil-to-lymphocyte ratio, systemic immunoinflammatory index, and prognostic nutrition index were factors affecting postoperative intestinal fistula in patients with CD. Multivariate logistic regression analysis showed that neutrophil-to-lymphocyte ratio, prognostic nutrition index, disease behavior, and Crohn disease activity index score were independent influencing factors. After assessing the validation set, the area under the curve was 0.899, indicating good predictive accuracy of the nomogram model. The prediction model developed in this study can effectively predict the risk of postoperative intestinal fistula.


Introduction
Crohn disease (CD) is a chronic nonspecific inflammatory disease of the bowel.Despite being a major treatment modality, surgery for CD is associated with more numerous and severe postoperative complications (anastomotic fistula, intestinal fistula, multisite infection, bleeding, and short bowel syndrome) than that for other gastrointestinal diseases.These complications affect the quality of life of patients, prolong the duration of hospitalization, and lead to reoperation. [1]Among them, intestinal fistula is a serious complication and a key factor leading to surgical failure that can be life-threatening if not treated properly.Thus, we retrospectively analyzed clinical data from patients with CD admitted for surgical treatment to investigate which preoperative clinical characteristics of patients were predictive of postoperative intestinal fistula.In addition, the risk factors for postoperative intestinal fistula in patients with CD were analyzed by univariate and multivariate logistic regression.A nomogram prediction model was also constructed to facilitate aggressive intervention against high-risk factors to reduce the incidence of postoperative intestinal fistula in patients with CD.This can enable patients to obtain greater benefits from treatment and provide a reference for predicting postoperative intestinal fistula.

General characteristics
A retrospective multicenter case-control study design was used.The clinical data of patients with CD who underwent surgical treatment between September 2019 and September 2021 at the Third Xiangya Hospital of Central South University, Xiangya Hospital of Central South University, and the Sixth Affiliated Hospital of Sun Yat-sen University were collected.In total, 240 patients were included.The diagnostic criteria established by the European Crohn's and Colitis Organisation were used for diagnosing CD [2] and involved a combination of clinical manifestations and endoscopic, pathological, and imaging findings from patients.Medical record systems were used to retrieve the data of the 240 hospitalized patients.The patients were randomly divided into a training (168 patients [70%]) and a validation set (72 patients [30%]).

Ethics
The study was approved by the ethics committee of the Sixth Affiliated Hospital, Sun Yat-Sen University (Ethics Number: 2023ZSLYEC-176).

Inclusion and exclusion criteria
Inclusion criteria were as follows: (1) confirmed diagnosis of CD, (2) initial bowel resection, and (3) postoperative follow-up period of 90 days.Exclusion criteria were: (1) having only undergone strictureplasty, (2) having only undergone small bowel stoma or colostomy, (3) having only undergone perianal abscess or anal fistula surgery, (4) dying during the perioperative period, and (5) having an anastomotic fistula at postoperative follow-up.

Follow-up and study endpoints
The date of initial surgery for patients with CD between September 2019 and September 2021 was used as the starting point of the study.The follow-up period was 90 days.Development of intestinal fistula within or at 90 days after surgery was used as the study endpoint.Follow-up was conducted by outpatient visits, telephone inquiries, or hospitalization.

Diagnosis of postoperative intestinal fistula
A postoperative intestinal fistula means that the patient developed an enterocutaneous fistula within 90 days after surgery.The diagnosis was confirmed by a combination of endoscopy, imaging (e.g., computed tomography, ultrasound, magnetic resonance imaging), and subsequent laparotomy findings.

Study indicators
The required clinical information was ascertained through the medical record system in accordance with the inclusion and exclusion criteria.The main components included: ( The accuracy of the model was evaluated using calibration curves, and the predictive ability of the model was validated using the validation set.Differences with P < .05were considered statistically significant.

General characteristics of patients in the training set
A total of 240 patients with CD were included in this study.Among them, 168 (70%) were in the training set, and 72 (30%) were in the validation set.Of the 168 patients with CD, 139 (82.73%) were male, and 29 (17.27%) were female.The average disease duration was 7 months (range: 1-36 months) from the diagnosis of CD to the first surgical treatment.The mean BMI was 21.32 ± 5.24 kg/m 2 .There were 46 cases of postoperative intestinal fistula (39 males and 7 females, male-to-female ratio: 5.57:1).There were 122 patients without postoperative intestinal fistula (100 males and 22 females, male-to-female ratio: 4.55:1).

Univariate analysis of factors influencing postoperative intestinal fistula in the training set
Univariate analysis showed that disease site, disease behavior, disease activity, abdominal abscess, intestinal perforation, intestinal obstruction, hormonal drug therapy, infliximab therapy, BMI, white blood cell count, platelet, neutrophils, lymphocyte, C-reactive protein, erythrocyte sedimentation rate, ALB, NLR, PLR, CAR, SII, and PNI were factors influencing the development of postoperative intestinal fistula in patients with CD (P < .05)(Tables 1-3).In contrast, sex, age of onset, duration of disease, history of appendectomy, perianal lesions, 5-mesalazine treatment, immunosuppressants, hemoglobin, hematocrit, eosinophil count, basophil count, globulin, D-dimer, emergency or elective surgery, open or laparoscopic surgery, type of anastomosis, EBV infection, cytomegalovirus infection, and C difficile infection were not factors that influenced the development of postoperative intestinal fistula in patients with CD (P > .05)(Tables 1 and 2).

Multivariate analysis of factors influencing postoperative intestinal fistula in the training set
Multivariate logistic regression analysis was performed using statistically significant indicators from the univariate analysis as the independent variables and the development of postoperative intestinal fistula as the dependent variable.The analysis showed that NLR, PNI, disease behavior (B2), and CDAI scores were independent factors influencing the development of postoperative intestinal fistula (Table 4).The results showed that B2 (P = .001,odds ratio (OR) = 6.305, 95% confidence interval (CI): 2.178-18.259),high NLR (P = .006,OR = 1.082, 95% CI: 1.023-1.144),and the CDAI scores [mildly active (P = .003,where p is the probability of postoperative intestinal fistula, with values closer to 1 indicating a greater likelihood of the patient developing postoperative intestinal fistula, and values closer to 0 indicating a lower likelihood.

Nomogram for disease risk prediction
The independent risk factors with P < .05associated with postoperative intestinal fistula based on multivariate logistic regression analysis were NLR, PNI, disease behavior (B2), and CDAI scores.These were incorporated into further model construction to construct a nomogram for calculating the risk from each factor (Fig. 1).Based on the clinical characteristics of patients with CD, a line perpendicular to the scale was made at the scores of each risk factor to obtain the points for each item, with higher scores indicating a higher probability of postoperative intestinal fistula in patients with CD.The scores of each risk factor were added to obtain the total score.

Evaluation of the nomogram prediction model
The prediction model was evaluated by plotting a receiver operating characteristic curve and calculating the AUC values.The AUCs of the training and validation sets were 0.863 and 0.899, respectively, suggesting good predictive ability (Fig. 2).
The nomogram prediction model was validated using the validation set.The results showed a C-index of 0.899 (95% CI: 0.830-0.968,P < .001).Generally, a C-index between 0.50 and 0.70 indicates low accuracy, between 0.71 and 0.90 indicates moderate accuracy, and above 0.90 indicates high accuracy; thus, the nomogram has a good predictive value.Next, the calibration curves for the nomogram prediction model of the training and validation sets were plotted (Fig. 3).In addition, the Hosmer-Lemeshow test for goodness of fit showed X 2 = 10.255 and P = .248for the training set and X 2 = 3.652 and P = .887for the validation set.As P was >.05, there was no significant difference between the actual and calibration curves, suggesting that the model has a good predictive ability.

Discussion
Among patients with CD, 90% undergo surgery during disease progression, and 50% require a second operation.Thus, surgery remains a major treatment modality for CD. [3]There is currently a lack of domestic and international multicenter clinical studies reporting on the development of enterocutaneous fistula following CD surgery with predictive models.Some singlecenter studies from China have reported the incidence of postoperative complications of CD to be 5.92% to 32.3%, among  which the incidence of enterocutaneous fistula accounted for 8.3% to 58.6% of the total complication rate. [4]Previous international studies have reported the incidence of postoperative complications of CD to be 5.0% to 40.9%, with the incidence of enterocutaneous fistula accounting for 6.0% to 76.4% of the total complication rate. [5,6]Postoperative intestinal fistula can cause changes such as abdominal infection, malnutrition, and multi-organ failure.Given the severity of this complication, the prevention of postoperative intestinal fistula in patients with CD warrants attention.The findings of previous domestic and international studies indicate that emergency surgery, type of anastomosis, disease activity, increased hematocrit, preoperative anemia, preoperative malnutrition, decreased preoperative body mass, preoperative azathioprine treatment, preoperative steroid treatment, preoperative antitumor necrosis factor-α treatment, and perforation lesions were considered factors influencing the development of various complications after surgery in patients with CD.[9] Thus, the present study combined data from 3 inflammatory bowel disease centers in China to investigate the factors influencing the development of postoperative intestinal fistula in patients with CD and to develop a predictive model.
Various single serological indicators have low specificity and large errors in evaluating postoperative complications in patients with CD.In light of this, the aim of the present study was to evaluate disease activity and the development of postoperative complications in CD by establishing composite serologic indexes.By collecting clinical data and serological indicators of patients with CD from 3 large tertiary hospitals, it was found that NLR, PLR, CAR, SII, and PNI were all factors influencing the development of postoperative intestinal fistula.High NLR and low PNI were risk factors for postoperative intestinal fistula; the higher the NLR, the greater the risk of postoperative intestinal fistula, and the higher the PNI, the lower the risk of postoperative intestinal fistula.NLR and PLR can be determined easily from complete blood count and have been confirmed as biomarkers of inflammation and to be important in disease prognosis.Several studies have reported their correlation with the prognosis of inflammatory diseases such as acute/ chronic pancreatitis; hepatitis; cancers of the gastrointestinal tract, liver, and pancreas; as well as cardiovascular disease, and it has also been used to assess CD activity. [10]Inflammation and cancer have been suggested to cause tissue necrosis, which can elevate NLR and increase inflammatory mediators in the body, thereby triggering inflammatory cascades. [11]Lymphocytes are major inflammatory cells of the immune system that can kill pathogenic microorganisms when inflammation is present but  are also accompanied by the depletion of lymphocytes, so NLR can be used as an indicator of inflammation in determining the prognosis of patients with inflammatory diseases.PNI is an indicator that responds to both the nutritional and immune status of the body, and it is often used for determining the prognosis and severity of disease in patients with chronic diseases. [12]A study showed that lower preoperative PNI levels are a marker of disease activity in patients with CD. [13] Clinicians should be aware of the perioperative management of CD patients with low PNI.Therefore, the management of antibiotics and enteral and parenteral nutrition is particularly important.Moreover, it is important to optimize the implementation of prevention strategies at early stages before the operation to reduce the development of postoperative enterocutaneous fistula in patients with CD.
The results of the present study showed that the CDAI score is a factor influencing the development of postoperative enterocutaneous fistula in patients with CD.Multivariate logistic regression analysis suggested that higher disease activity resulted in a higher risk of postoperative intestinal fistula.The CDAI score can be used for assessing current disease activity in patients with CD, as well as for dynamic monitoring of changes in disease activity after CD treatment.It can also indicate the recurrence of symptoms after surgery, making it a benchmark for measuring disease severity, clinical response, and remission rates.A study showed a higher incidence of postoperative infectious complications in patients with active CD than in patients in remission. [14]he present study suggested that disease behavior influences the development of postoperative intestinal fistula in patients with CD.Multivariate logistic regression analysis suggested that the risk was significantly higher in patients with stricturing CD than in patients with non-stricturing and nonperforating CD.Perforating CD was not an independent risk factor for the development of postoperative intestinal fistula.Wang et al [15] included 142 Chinese patients with CD and suggested that patients with perforating CD are more likely to develop recurrence after surgery.Perforation lesions in the intestinal wall can involve adjacent organs and tissues, forming enterovesical or rectovaginal fistulas and leading to abdominal abscesses.In the present study, we found that patients with stricturing CD are more likely to develop intestinal fistulas than patients with perforating CD.This may be due to the combination of mucosal inflammation, the release of associated molecular mediators, and increased growth factor levels that promote the recruitment and proliferation of smooth muscle cells, stellate cells, and myofibroblasts in patients with CD, leading to intestinal fibrosis.In addition, intestinal stricture due to CD differs from intestinal obstruction due to other diseases, and anti-inflammatory therapy alone or small bowel endoscopic strictureplasty may not be an effective treatment.Moreover, stricture may occur in other parts of the bowel segment as the disease progresses, even after surgical removal of the strictured bowel segment.
There is a lack of domestic and international predictive models related to the development of postoperative intestinal fistula in patients with CD.Therefore, it is important to construct practical risk models with high predictive value to help stratify at-risk patients.Based on this predictive model, clinicians can identify patients at higher risk of developing enterocutaneous fistula after surgery at an early stage, which is also significant for earlier recovery after surgery.Studies have shown that nomograms have high accuracy and ease of application in predicting disease occurrence. [16]The nomogram defines a score for each independent variable based on the magnitude of the regression coefficients of all independent variables.The scores of all independent variables are then added to yield a total score, which is used to calculate the probability of postoperative intestinal fistula for each patient.In the present study, 4 independent factors were identified based on multifactorial logistic regression analysis, namely disease behavior (B2), NLR, PNI, and CDAI scores.These were integrated into a nomogram model for predicting the development of postoperative intestinal fistula, with a C-index of 0.899 (95% CI: 0.830-0.968,P < .001)obtained after evaluation of the validation set.Finally, similar results were obtained in the Hosmer-Lemeshow goodness-of-fit test, indicating that the model has good predictive properties.
As a retrospective analysis, this study had some limitations.First, the study results may have been influenced by factors such as recall bias and follow-up timeframe.Second, the present study only observed the development of postoperative intestinal fistula, whereas the reoperation rate, hospitalization rate, and the development of other complications were not analyzed.Therefore, we expect that more data from patients with CD in inflammatory bowel disease centers and more comprehensive clinical data from patients will be collected in future prospective cohort studies to confirm the accuracy and utility of this prediction model.In conclusion, there is a lack of domestic and international multicenter studies and nomogram models of risk factors for the development of postoperative intestinal fistula after CD.Studying the pattern of CD progression, identifying independent influencing factors for postoperative intestinal fistula in CD, and facilitating aggressive intervention against high-risk factors, thus reducing the incidence of postoperative intestinal fistula in patients with CD, enables patients to reap greater benefits from treatment.The predictive model was validated externally using the validation set to effectively predict the risk of postoperative enterocutaneous fistula, which partially informs the development and adjustment of perioperative treatment plans and management strategies for patients with CD.Individuals at higher risk of developing enterocutaneous fistula should be provided early symptomatic interventions to reduce the risk of postoperative enterocutaneous fistula, thus allowing them derive greater benefit from treatment and reduce suffering.

Figure 2 .
Figure 2. Receiver operating characteristic curve of the training and validation sets.

Figure 3 .
Figure 3. Calibration curve of the (A) modeling group and (B) prediction group.

Table 1
Univariate analysis of factors influencing postoperative intestinal fistula in patients with Crohn disease (categorical variables).

Table 3
Univariate analysis of factors influencing intestinal fistula after Crohn disease surgery (count data of complex hematological indicators).

Table 4
Multivariate analysis of factors influencing postoperative intestinal fistula in patients with Crohn disease.